The identification of individuals at high risk for cancer is an important goal of the molecular genetic study of cancer both for genetic screening and early detection of cancers with the resulting improvement in treatment outcome. The study of secondary genetic events that occur in the somatic cells of predisposed individuals during tumorigenesis may also provide insight into the underlying mechanisms of cancer which will have an impact on the treatment and screening of these individuals. If inheritance of a p53 mutation results in predisposition to many different tumors, then the timing and nature of the secondary somatic events must determine the type of tumor that actually occurs and the age of occurrence. The necessity of acquiring additional somatic changes may explain the age-specific and tumor-type variability of penetrance in tumors from predisposed individuals. Homozygous mutations and tumor-specific losses of constitutional heterozygosity have been reported for several recessive oncogenes in studies of sporadic tumors.As well, sporadic tumors have been shown to undergo mutations consistent with a role for genomic imprinting during tumor formation. By examining all of these secondary genetic changes and the parental origins of the retained alleles in tumors from predisposed individuals,we may understand the mechanisms which determines the timing and type of tumors that arise in the predisposed individuals. Finally, it is not known whether all germinal sequence alterations found in the p53 or RB1 genes constitute cancer predisposing mutations. Developing a functional test to determine the effect of the base sequence changes would be useful in assessing the genetic risk of these sequence changes.